The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway, comprised of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and downstream signaling adaptors, plays an essential role in protective immune defense against microbial DNA and internal damaged-associated DNA and is responsible for various immune-related diseases. After binding with DNA, cytosolic cGAS undergoes conformational change and DNA-linked liquid-liquid phase separation to produce 2'3'-cGAMP for the activation of endoplasmic reticulum (ER)-localized STING. However, further studies revealed that cGAS is predominantly expressed in the nucleus and strictly tethered to chromatin to prevent binding with nuclear DNA, and functions differently from cytosolic-localized cGAS. Detailed delineation of this pathway, including its structure, signaling, and regulatory mechanisms, is of great significance to fully understand the diversity of cGAS-STING activation and signaling and will be of benefit for the treatment of inflammatory diseases and cancer. Here, we review recent progress on the above-mentioned perspectives of the cGAS-STING signaling pathway and discuss new avenues for further study.
先天免疫系统是宿主免疫防御的第一道防线，其通过多种机制保护宿主抵御外源病原入侵及内源损伤。cGAS-STING信号通路是先天免疫的重要通路之一，其由环磷酸鸟苷-磷酸腺苷酸合成酶（cyclic GMP-AMP synthase, cGAS）、干扰素基因刺激物（stimulator of interferon gene，STING）和一系列下游信号转导接头分子及效应分子共同组成。cGAS是一种DNA感受器，在与DNA结合后，细胞质中的cGAS发生构象变化并由DNA介导聚集形成液-液相分离。随后，cGAS催化ATP和GTP合成第二信使2'3'-cGAMP，以激活定位于内质网（endoplasmic reticulum, ER）的STING，诱导STING转运并介导下游I型干扰素的产生。近年来研究发现，除了定位于细胞质发挥DNA识别受体的功能外，cGAS更主要在细胞核中表达，并被束缚于染色质以防止其与核DNA的结合，避免自身免疫疾病的发生。在功能上，核定位的cGAS与细胞质cGAS也具有较大差异。此外，cGAS-STING信号通路的异常也与多种疾病的发生密切相关。因此，对于cGAS-STING的结构，信号转导和调控机制方面的系统性探究，将更有助于我们深入了解该信号通路的活化和信号传递机制，并将为免疫相关疾病和肿瘤的治疗提供新的方向。基于此，该文详细综述了cGAS-STING信号通路目前的研究进展，并对其将来的研究方向提出展望。.
Keywords: Diseases; Post-translational modification; STING; Signaling; Structure; cGAS.